KR20160141845A - Optically active pde10 inhibitor - Google Patents

Abstract

The present invention relates to a process for the preparation of 1- (5-4-chloro-3,5-dimethoxyphenyl) furan-2-yl) -2-ethoxy- 2- 4- 4- (S) -1- (5-4-chloro-3,5-dimethoxyphenyl) furan-2-yl) -2- 2- (4- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl) ethanone.
The present invention also relates to a process for the preparation of (S) -1- (5-4-chloro-3,5-dimethoxyphenyl) 3,4-thiadiazol-2-yl) phenyl) ethanone crystal structure; (S) -1- (5-4-chloro-3,5-dimethoxyphenyl) furan-2-yl) -2-ethoxy- 2- 4- 4- Diazol-2-yl) phenyl) ethanone; (S) -1- (5-4-chloro-3,5-dimethoxyphenyl) furan-2-yl) -2-ethoxy- 2- 4- 4- Diazo-2-yl) phenyl) ethanone is used to inhibit (inhibit) PDE10; (S) -1- (5-4-chloro-3,5-dimethoxyphenyl) furan-2-yl) -2-ethoxy- 2- 4- 4- Diazol-2-yl) phenyl) ethanone; 2- (4-chloro-3,5-dimethoxyphenyl) furan-2-yl) -2-ethoxy- Thiadiazol-2-yl) phenyl) ethanone. ≪ / RTI >

Description

Optically active PDE10 inhibitor {OPTICALLY ACTIVE PDE10 INHIBITOR}

This application claims the benefit of U.S. Provisional Application No. 62 / 047,569, filed September 8, 2014, and U.S. Provisional Application No. 61 / 985,381, filed April 28, Under §119 (e). These U.S. Provisional Applications are incorporated herein by reference in their entirety.

The present invention provides an enantiomerically pure compound having activity as a PDE inhibitor, a composition containing said enantiomerically pure compound, and an enantiomerically enriched enantiomerically enriched compound as described above in a warm- To a method of treating various diseases by administering a pure compound. Specifically, the present invention relates to the use of (S) -1- (5-4-chloro-3,5-dimethoxyphenyl) Methyl-1,3,4-thiadiazol-2-yl) phenyl) ethanone (Compound 2001).

The cyclic nucleotide phosphate diester hydrolases (PDEs) are representative of the enormous superfamily enzymes. PDEs are known to have a modular architecture with a conserved catalytic domain near the carboxyl end and often a regulatory domain or motif in the vicinity of the amino end. The PDE superfamily has been recently shown to contain more than 20 different genes that subgroup 11 PDE families (Lugnier, C, "Ringed Nucleotide Phosphate Diester Hydrolyzate (PDE) Superfamily: New Targets for the Development of Antibodies ", Pharmacol Ther., March 2006; 109 (3): 366-98).

PDE10, a recently discovered PDE, has been reported simultaneously by three independent groups (Fujishige et al., "Cloning and Characterization of a New Human Phosphate Diester Hydrolase (PDE10A) Hydrolyzing Both cAMP and cGMP" J Biol Chem 1999, 274: 18438-18445; Loughney et al., "Isolation and Characterization of PDE10A, a New Human 3 ', 5'-Ring Nucleotide Phosphate Diester Hydrolase" Gene 1999, 234: 109-117) ; And Soderling et al. ("Isolation and Characterization of PDE10A, a family of double substrate phosphoryl diester hydrolase genes, Proc Natl Acad Sci USA 1999, 96: 7071-7076). PDE10 has the ability to hydrolyze both cAMP and cGMP; The K _m for cAMP is approximately 0.05 μM while the K _m for cGMP is 3 μM. In addition, the V _max for cAMP hydrolysis is five times lower than the V _max for cGMP hydrolysis. Because of this kinetics, cGMP hydrolysis by PDE10 is strongly inhibited by cAMP in vitro, because PDE10 can function as a cAMP-inhibited cGMP phosphoric acid diester hydrolase in vivo It is suggested that Unlike the PDE8 or PDE9, PDE10 is inhibited by IBMX with the IC _{50 (50%} inhibitory concentration) of 2.6μM (Solderling and literature [ "cAMP and cGMP signaling in the regulation of Beavo: New phosphate diester hydrolase And New Functions "Current Opinion in Cell Biology, 2000, 12: 174-179).

PDE10 contains two amino-terminal domains similar to the cGMP-binding domains of PDE2, PDE5 and PDE6, which are conserved across various proteins. Due to the broad conservation of these domains, it is currently being used for the GAF domain (for the following GAF proteins: cGMP-conjugated phosphate diester hydrolases, cyanobacterial anabenylacylase adenylyl cyclase); And Escherichia coli transcriptional regulatory fhlA). Although the GAF domain also binds cGMP in PDE2, PDE5 and PDE6, this is probably not the primary function of this domain in all cases (e.g., E. coli is not considered to synthesize cGMP). Interestingly, a study of in vitro binding of PDE10 indicates that the dissociation constant (K _d ) for cGMP binding far exceeds 9 μM. Since the in vivo concentration of cGMP is not considered to reach such high levels in most cells, the affinity of PDE10 for cGMP is increased by modulation, or the major function of the GAF domain in PDE10 is increased by cGMP binding It seems to be another function.

Inhibitors of PDE family enzymes are widely available for the treatment of a wide range of indications. Reported therapeutic uses for PDE inhibitors include allergies, obstructive pulmonary disease, hypertension, renal cancer, angina, congestive heart failure, depression and erectile dysfunction (see WO 01/41807 A2). Other PDE inhibitors have been found to be therapeutic for ischemic heart disease (see U.S. Patent No. 5,693,652). More specifically, PDE10 inhibitors have been found to be useful in the treatment of certain neurological and psychiatric disorders, including Parkinson's disease, Huntington's disease, asthenia, retinopathy, drug-induced psychosis, panic disorder, and obsessive compulsive disorder (see U.S. Publication No. 2003/0032579 ). PDE10 has been shown to be present at high levels in neurons in the brain region that are closely associated with a number of neurological and psychiatric disorders. Due to the inhibition of PDE10 activity, the levels of cAMP and cGMP are increased in the neurons, thereby improving the ability of these functioning neurons. Thus, inhibition of PDE10 is believed to be useful in the treatment of various diseases or disorders that are cured by increasing cAMP and cGMP levels in neurons, including neurological disorders, mental disorders, anxiety disorders, and / .

Compounds of formula (I) are well known PDE10 inhibitors:

In formula (I), A is

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ego;

;

R ₁ is C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 aralkyl, _{aryl, - (CH 2) n O} (CH 2) m CH 3 or _{- (CH 2) n N (} CH 3 ) ₂ ;

R ₂ is (i) substituted or unsubstituted aryl or (ii) substituted or unsubstituted heterocyclyl;

R ₃ is substituted or unsubstituted aryl;

R4 is hydrogen, _C1-6 alkyl or _C1-6 haloalkyl;

n is 1, 2, 3, 4, 5 or 6;

m is 0, 1, 2, 3, 4, 5 or 6;

Compounds of formula (II) below are known potent PDE10 inhibitors:

In formula (II), Q is S or O;

X is Cl or Br;

R ¹ , R ² and R ³ are each independently C _1-6 alkyl.

Compounds of formula (III) below are known PDE10 inhibitors:

In formula (III), Q is S or O;

X is Cl or Br.

Compounds having the structures of the above formulas (I), (II) and (III) and the following compound 1001 belong to the category of PDE10 inhibitors described in PCT International Publication No. WO 2011/112828. 2-ethoxy-2- (4- (5-methyl-1,3,4-thiadiazol-2-yl) Yl) phenyl) ethanone (Compound 1001) is specifically described as Compound No. 65-10.

Although technological advances have been made to inhibit PDE10, there remains a need for the field of PDE10 inhibitors and the need for treatment of various diseases and / or symptoms cured by PDE10 inhibitors. It is an object of the present invention to provide an enantiomerically pure compound, a method of using enantiomerically pure compounds, and a composition for inhibiting PDE10 comprising an enantiomerically pure compound.

A brief summary of the invention

The present invention relates to a pure enantiomer of compound 1001, specifically compound 2001 and compound 3001. The present invention also relates to the crystal structure of compound 2001, a pharmaceutical composition comprising compound 2001, a method of inhibiting (inhibiting) PDE10 using compound 2001, a method of preparing compound 2001, and a specific individual intermediate And a method for producing the same.

In one embodiment of the present invention, the present invention relates to a compound having the structure, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a further embodiment of the present invention, compound 2001 is pure (e.g., exists at an enantiomeric excess of at least about 98%).

In a further embodiment of the invention, compound 2001 is substantially enantiomerically pure.

In a further embodiment of the invention, compound 2001 comprises at least about 80%, at least about 90%, at least about 95%, or at least about 99% by weight of a given enantiomer (e.g., Is present at an enantiomeric excess of greater than about 60%, greater than about 80%, greater than about 90%, or greater than about 98%.

In one embodiment of the present invention, the present invention relates to a compound having the structure: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a further embodiment of the invention, compound 3001 is optically ideal (e.g., present at an enantiomeric excess of greater than about 98%).

In a further embodiment of the invention, compound 3001 is substantially free of enantiomers.

In a further embodiment of the invention, the compound 3001 comprises at least about 80%, at least about 90%, at least about 95%, or at least about 99% by weight of the desired enantiomer (e.g., the desired enantiomer Is present at an enantiomeric excess of greater than about 60%, greater than about 80%, greater than about 90%, or greater than about 98%.

In another embodiment of the present invention, the present invention relates to a compound having the following structure in crystalline form.

In a further embodiment of the present invention, the crystalline form of Compound 2001 is about 8, about 11.2, about 12, about 13.8, about 14.3, about 16.5, about 17.8, about 18, about 19.4, about 21.2, about 21.6, about 22.2 , About 150K, such as 150K + 10K or 150K + 1K, which provides a characteristic X-ray powder diffraction pattern having a major 2 &thetas; peak at about 22.8, about 23.9, about 25.6, ≪ RTI ID = 0.0 > X-ray powder diffraction < / RTI >

In a further embodiment of the present invention, the crystalline form of compound 2001 has an X-ray powder diffraction pattern substantially identical to that shown in FIG.

In another embodiment of the present invention, the present invention relates to a pharmaceutical composition comprising compound 2001 and a pharmaceutically acceptable carrier or diluent.

In another embodiment of the present invention, the present invention relates to a method of inhibiting PDE10 in a warm-blooded animal, comprising administering to the animal an effective amount of compound 2001 or a pharmaceutical composition comprising the same.

In a further embodiment of the present invention, the present invention relates to a neurological disorder of a warm-blooded animal with a neurological disorder, comprising administering to the animal an effective amount of compound 2001 or a pharmaceutical composition comprising the same, Anxiety disorder, Parkinson ' s disease, Huntington's disease, Alzheimer's disease, encephalitis, phobia, epilepsia, Aphasia, Bell's palsy, cerebral palsy, sleep disorder, pain, Tourette's syndrome, schizophrenia, delusional disorder, ), Bipolar disorder, post-traumatic stress disorder, drug-induced psychosis, panic disorder, obsessive-compulsive disorder, attention deficit disorder attention-defi cit disorder, disruptive behavior disorder, autism, depression, dementia, epilepsy, insomnia, and multiple sclerosis. ≪ / RTI >

In a further embodiment of the present invention, the neurological disease is asthma.

In a further embodiment of the invention, the neurological disorder is post-traumatic stress disorder.

In one embodiment of the present invention, the present invention provides a process for preparing a compound of the formula (II-a) according to the general reaction scheme (I)

In formula (II-a), Q is S or O,

X is Cl or Br,

R ¹ , R ² and R ³ are each independently C _1-6 alkyl;

Converting the boronic acid A1 to carbaldehyde B1 via activation of boronic acid using the activating reagent A2;

Converting the carbaldehyde B1 to an acetal Cl under acid catalysis using an appropriate orthoformate source;

Converting the acetal C1 to nitrile D1 via catalyzed cyanation using a metal catalyst and a cyanide source;

Hydrolyzing D1 with a suitable acid to provide carboxylic acid E1;

Converting the carboxylic acid E1 to an amide F1 using a suitable base, a suitable coupling agent and an amine source;

Converting an amide F1 to a compound of formula (II) using an anionic coupling agent having a H1 structure,

M is a Group 1 metal, a Group II metal, Cu or Zn;

R, R ² and R ³ are each independently C _1-6 alkyl;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Separating the compound of formula (II-a) from the compound of formula (II-b) by chiral HPLC; And

Optionally converting the compound of formula (II-a) to a salt.

In one embodiment of the present invention, the compound of formula (II-a) is the following compound 2001:

In one embodiment of the present invention, the present invention provides a process for preparing a compound of the formula (III-a) according to the general reaction scheme (III)

In formula (III-a), Q is S or O and X is Cl or Br;

Scheme (III)

Converting the boronic acid A1 to a carbaldehyde B1 through activation of a boronic acid using an activating reagent A2;

Converting the carbaldehyde B1 to acetal C1-1 under acid catalysis using an appropriate orthoformate source;

Converting the acetal C1-1 to nitrile D1-1 via catalytic cyanation using a metal catalyst and a cyanide source;

Hydrolyzing D1-1 with a suitable acid to provide carboxylic acid E1-1;

Converting the carboxylic acid E1-1 to the amide F1-1 using a suitable base, a suitable coupling agent and an amine source;

Converting an amide F1-1 to a compound of formula (III) using an anionic coupling agent having a H1-1 structure,

M is a Group 1 metal, a Group II metal, Cu or Zn;

R is C _1-6 alkyl;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Separating the compound of formula (III-a) from the compound of formula (III-b) by chiral HPLC; And

Optionally converting the compound of formula (III-a) to a salt.

In one embodiment of the invention, the compound of formula (III-a) is the following compound 2001:

The above-described embodiments of the present invention and other embodiments will be apparent from the following description of the detailed description. To this end, reference will be made herein to specific background information, processes, compounds and / or compositions which are described in more detail in the specification, each of which is incorporated herein by reference in its entirety.

Figure 1 is XRPD of dioxane solvate of compound 2001 measured at about 150K < RTI ID = 0.0 > 1K. ≪ / RTI >
Figure 2 is a packing diagram of the dioxane solvate of compound 2001 viewed along the crystallographic a axis.
Figure 3 is a packing diagram of the dioxane solvate of compound 2001 seen along the crystallographic b axis.
Figure 4 is a packing diagram of the dioxane solvate of compound 2001 seen along the crystallographic c axis.
5 is an ORTEP plot of dioxane solvate of compound 2001;
Figure 6 shows the inhibition of human PDE10 by compound 1001.
Figure 7 shows the inhibition of human PDE10 by Compound 1001, Compound 2001 and Compound 3001.

Justice

Terms not specifically defined herein have meanings assigned to those of ordinary skill in the art in light of the description and context. However, as used throughout this application, unless stated otherwise, the following terms have the following meanings:

And "amino" means -NH ₂ radical.

"Cyano " means a -CN radical.

"Hydroxy" or "hydroxyl" means an -OH radical.

"Imino" means an = NH substituent.

"Nitro" means the -NO ₂ radical.

"Oxo" means a = O substituent.

"Thioxo" means an = S substituent.

"C _1-6 alkyl" means a straight or branched, cyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon radical having one to six carbon atom (s). Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the like. Representative saturated branched alkyls include isopropyl, sec-butyl, isobutyl, Pentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Exemplary unsaturated cyclic alkyls include cyclopentenyl, cyclohexenyl, and the like. Unsaturated alkyl contains one or more double or triple bonds between adjacent carbon atoms (each referred to as "alkenyl" or "alkynyl"). Representative straight and branched chain alkenyls include, but are not limited to, ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-butenyl, 2,3-dimethyl-2-butenyl and the like. Representative straight chain and branched chain alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

"C _1-6 alkylene" or "C _1-6 alkylene chain" is saturated or unsaturated (i. E. Contains one or more double bonds and / or triple bonds) and contains one to six carbon atom Linking the remainder of the molecule to a radical consisting only of carbon and hydrogen (e.g., methylene, ethylene, propylene, n-butylene, ethenylene, prophenylene, n-butenylene, propynylene, n-butynylene, etc.) Means a straight or branched divalent hydrocarbon chain. The alkylene chain is attached to the remainder of the molecule through a single bond or a double bond and is attached to the radical group through a single bond or a double bond. The point of attachment of the alkylene chain to the remainder of the molecule and the point of attachment of the alkylene group to the radical group may be through one carbon in the chain or any two carbons.

"C _1-6 alkoxy" means a group of the formula -OR _a where R _a is an alkyl radical as defined above (e.g., methoxy, ethoxy, etc.).

"Aryl" is a hydrocarbon ring system radical comprising hydrogen, from 6 to 18 carbon atoms, and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic or heterocyclic ring systems including fused or bridged ring systems. The aryl radical is selected from the group consisting of acetylacetylene, acenaphthylene, acesulfatrylene, atracene, azulene, benzene, chrysene, fluorene anthane, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, But are not limited to, aryl radicals derived from naphthalene, phenanthrene, playaden, pyrene and triphenylene.

"C _1-6 aralkyl" means a radical of the formula -R _b -R _c wherein R _b is an alkylene chain as defined above and R _c is one or more aryl radicals as defined above , Benzyl, diphenylmethyl, etc.).

"Cycloalkyl" or "carbocyclic ring" may include fused or bridged ring systems and have 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, Means a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen which is unsaturated and attached to the remainder of the molecule by a single bond. Exemplary monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1]

"Halo" or "halogen" means bromo, chloro, fluoro or iodo.

"C _1-6 haloalkyl" means a C _1-6 alkyl radical as defined above substituted with one or more halo radicals as defined above (e.g., trifluoromethyl, difluoromethyl, trichloromethyl, , 2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like).

The term "enantiomerically pure" with reference to a particular stereoisomer (e.g., compound 2001) means that there is substantially no enantiomer of the particular stereoisomer (e.g., compound 3001). That is, "enantiomerically pure" stereoisomers have an enantiomeric excess of greater than about 98%, greater than about 98.5%, greater than about 99%, greater than about 99.5%, greater than about 99.8%, or greater than about 99.9%.

"Heterocycle" or "heterocyclyl" is a 4- to 7-membered monocyclic or 7-membered monocyclic ring containing 1 to 4 heteroatom (s) independently selected from nitrogen, Means a heterocycle of one to ten membered ring, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized, wherein any hetero ring is fused to the benzene ring Lee, Won Hwan. The heterocycle may be attached by any heteroatom or carbon atom. Aromatic hetero ring refers to "heteroaryl" in the present specification and includes furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, iso Wherein the heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl But are not limited to, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, In addition to the heteroaryls listed above, the heterocycle also includes morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, and the like. Also, the heterocycle includes benzothiophen-2-yl, 2,3-dihydrobenzo-1,4-dioxin-6-yl, benzo-1,3-dioxol-5-yl and the like.

The term "substituted " as used in this application (e.g., in the context of a substituted heterocyclyl or substituted aryl) means that at least one hydrogen atom is replaced by a substituent. In the description of the present invention, the term "substituent" means a substituent selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, imino, thioxo, amino, alkylamino, dialkylamino, alkyl, alkoxy, , heteroaryl, heteroaryl-alkyl, as well as heterocyclic and heterocycloalkyl _{-NR a R b, -NR a C} (= O) R b, -NR a C (= O) NR a NR b, -NR a C _{(= O) OR b, -NR} a SO 2 R b, -C (= O) R a, -C (= O) OR a, -C (= O) NR a R b, -OC (= O) _{NR a R b, -OR a,} -SR a, -SOR a, -S (= O) 2 R a, -OS (= O) 2 R a, -S (= O) 2 OR a, = NSO 2 R _a and -SO ₂ NR _a R _b . In the above formulas, R _a and R _b may be the same or different and independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl. In addition, the substituents described above may be further substituted with one or more of the foregoing substituents.

The compounds of the present invention can generally be used as free acids or as free bases. Alternatively, the compounds of the present invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods known in the art and may be formed from organic acids and inorganic acids. Suitable organic acids include those derived from maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, Stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid. Base addition salts include those formed using carboxylate anions and include not only cations selected from alkali metals such as lithium, sodium, potassium, and alkaline earth metals such as magnesium, barium, calcium, Ion and a substituted derivative thereof (e.g., dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, etc.). Thus, the term "pharmaceutically acceptable salts" of formulas (I) & (II) is intended to include any and all permissible salt forms.

Embodiments of the Invention

In one embodiment of the invention, the PDE10 inhibitor comprises Compound 2001, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having the structure:

In a further embodiment of the invention, compound 2001 or a pharmaceutically acceptable salt, solvate or prodrug thereof is enantiomerically pure (e. G., Present at an enantiomeric excess of greater than about 98%).

In a further embodiment of the invention, compound 2001 or a pharmaceutically acceptable salt, solvate or prodrug thereof is substantially free of enantiomers.

In a further embodiment of the present invention, compound 2001 or a pharmaceutically acceptable salt, solvate or prodrug thereof is at least about 80%, at least about 90%, at least about 95%, or at least about 99% Enantiomer (e. G., The desired enantiomer is present at an enantiomeric excess of greater than about 60%, greater than about 80%, greater than about 90%, or greater than about 98%).

In one embodiment of the present invention, the present invention relates to a compound having the structure: or a pharmaceutically acceptable salt, solvate or prodrug thereof,

In a further embodiment of the invention, compound 3001 or a pharmaceutically acceptable salt, solvate or prodrug thereof is enantiomerically pure (e. G., Exists at an enantiomeric excess of greater than about 98%).

In a further embodiment of the invention, compound 3001, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is substantially free of enantiomers.

In a further embodiment of the invention, the compound 3001, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprises at least about 80%, at least about 90%, at least about 95%, or at least about 99% Enantiomer (e. G., The desired enantiomer is present at an enantiomeric excess of greater than about 60%, greater than about 80%, greater than about 90%, or greater than about 98%).

In one embodiment of the invention, the PDE10 inhibitor has the following structure in crystalline form:

In an embodiment of the present invention, the crystalline compound 2001 has a composition of about 8, about 11.2, about 12, about 13.8, about 14.3, about 14.5, about 15.5, Ray powder diffraction pattern comprising a major 2? Peak at about 16.5, about 17.8, about 18, about 19.4, about 21.2, about 21.6, about 22.2, about 22.8, about 23.9, about 25.6, about 27.5, about 29, .

In a further embodiment of the present invention, the crystalline compound 2001 has an X-ray powder diffraction pattern measured using CuK? Radiation at about 150K, e.g., 150K + 10K or 150K + 1K, Is substantially the same as what is provided.

The crystal structure of compound 2001 is measured by single crystal X-ray structural analysis.

Other alternate embodiments of the present invention are directed to a plurality of crystalline forms of compound 2001 wherein at least about 50%, at least about 75%, at least about 95%, at least about 99%, or at least about 100% (X-ray powder diffraction) spectrum defined in the above-mentioned XRPD (X-ray powder diffraction) spectrum. The presence of such an amount of crystalline compound 2001 is generally measurable using an XRPD analysis of the compound.

In another embodiment of the invention, pharmaceutical compositions containing compounds of structure 2001 are disclosed. For administration purposes, the compounds of the present invention may be formulated as pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise one or more compounds of the invention and a pharmaceutically acceptable carrier and / or diluent. A PDE10 inhibitor is present in an amount effective to treat a particular disease, i. E. A composition that is sufficient to achieve the desired PDE10 inhibition, preferably toxic to a warm-blooded animal. Generally, the pharmaceutical compositions of the present invention comprise a PDE10 inhibitor in an amount of from 0.1 mg to 1,250 mg, more usually from 1 mg to 60 mg per dose, depending on the route of administration. Appropriate concentrations and dosages can be readily determined by one of ordinary skill in the art.

Typically, the typical daily dosage will vary from 1 μg / kg to 100 mg / kg, preferably from 0.01 to 100 mg / kg, depending on the type and severity of the disease (eg whether or not it is due to more than one individual dose) Kg, more preferably from 0.1 to 70 mg / kg. Depending on the symptoms, in the case of repeated administrations for more than a few days, treatment continues until the inhibition of symptoms of the disease occurs as often as desired. However, other dosing regimens may be useful. This treatment process can be monitored by standard techniques and analytical methods. The specific recipe for the dosage unit form of the present invention is based on the unique characteristics of the active compound, the particular therapeutic effect to be achieved, the specificity to the field of compounding such as the active compound for treatment of the individual, Lt; / RTI >

Pharmaceutically acceptable carriers and / or diluents are well known to those skilled in the art. For compositions that are formulated as a liquid solution, the pharmaceutically acceptable carrier and / or diluent may include saline and sterile water, and may optionally contain antioxidants, buffers, bacteriostat, and other conventional additives. have. In addition, the compositions may be formulated as pills, capsules, granules or tablets containing excipients such as diluents, binders and lubricants in addition to PDE10 inhibitors. In addition, those of ordinary skill in the art will be able to administer the pharmaceutical composition of the present invention to a subject in a suitable manner, in accordance with accepted practice (e.g., as described in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990) Can be further formulated.

In another embodiment of the present invention, the present invention provides a method of treating a psychotic disorder, an anxiety disorder, a movement disorder and / or a neurological disorder (e.g. Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, Depression, dementia, psychotic disorder, depressive disorder, depressive disorder, obsessive compulsive disorder, attention deficit disorder, disruptive behavior disorder, autism, depression, dementia , Epilepsy, insomnia and multiple sclerosis). ≪ Desc / Clms Page number 2 > The method comprises administering a compound of the invention to a warm-blooded animal in an amount sufficient to treat the condition. The method preferably comprises systemically administering a PDE10 inhibitor of the invention in the form of a pharmaceutical composition as described above. As used herein, systemic administration includes, but is not limited to, oral administration and parenteral (including subcutaneous, intramuscular, intracranial, orbital, ophthalmic, intracerebral, intracapsular, Intravenous, intradermal, inhalational, transdermal, transmucosal, and rectal administration), as well as methods of intravenous administration, intravenous administration, intraperitoneal administration, intranasal administration, aerosol administration, intravenous administration,

Compound 1001 selectively inhibits PDE10 as compared to other human cyclic nucleotide phosphate diester hydrolase. The selectively inhibiting PDE10 includes PDE1A, PDE2A, PDE3A, PDE4A1A, PDE5A, PDE7A, PDE8A1, PDE9A2, PDE10A2 and PDE11A4. The selectivity profile of compound 1001 is shown in Table 1 below. The selectivity ratio is the IC ₅₀ value for each PDE enzyme divided by the IC ₅₀ for PDE10. Compound 1001 was 879 fold less potent in inhibiting PDE2 and 4800 fold less potent in inhibiting bovine PDE6 and 9200 fold in inhibiting PDE family 1, 3, 4, 5, 7, 8, 9 and 11 Or less.

Selectivity of Compound 1001 to inhibition of PDE10 PDE enzyme IC ₅₀  (nM) Selectivity ratio (times) 1A > 10000 > 16000 2A 545 879 3A > 10000 > 15000 4A1A > 10000 > 15000 5A 5740 9260 6 > 3000 > 4800 7A > 10000 > 16000 8A1 > 10000 > 16000 9A2 > 10000 > 16000 10A2 0.62 One 11A4 > 10000 > 16000

Although the enantiomers of compound 1001 are potent inhibitors of PDE10, compound 2001 is unexpectedly 13.2 times more potent than compound 3001 and 9.4 times more potent than racemic compound 1001.

For oral administration, suitable pharmaceutical compositions of PDE10 inhibitors include powders, granules, pills, tablets and capsules, as well as solutions, syrups, suspensions and emulsions. These compositions may also include flavoring agents, preservatives, suspending agents, thickening agents, emulsifying agents and other pharmaceutically acceptable additives and excipients. For parenteral administration, the compounds of the present invention may be formulated with aqueous injection solutions which may contain, in addition to the PDE10 inhibitors, buffers, antioxidants, bacterial growth inhibitors and other additives and excipients commonly used in aqueous injection solutions . The compositions of the present invention may be used in delivery systems that provide sustained-release or enhanced absorption or activity of therapeutic compounds (e. G., Injectable liposomes or hydrogel systems, oral or parenteral delivery microparticles , A nanoparticle or micelle system, or a staged capsule system for oral delivery).

) 및 관련된 비전형적 항정신병약들의 만성적인 사용은 비만 및 관련 증상들(예컨대, 당뇨병)을 비롯한 유의적인 대사성 부작용들과 연관된다. In a further advantage of the present invention, compound 2001 is expected to avoid or reduce metabolic side effects associated with conventional antipsychotic drugs, particularly the occurrence of therapeutically induced obesity. For example, Zyprexa, the most widely prescribed medication for suppurative treatment,

) And the chronic use of related atypical antipsychotics are associated with significant metabolic side effects, including obesity and related symptoms (e.g., diabetes).

In animals, subchronic treatment with olanzapine stimulates food intake and increases body weight, just as in humans. Moreover, olanzapine rapidly lowers blood leptin levels. Leptin is a satiety hormone produced from adipose tissue, and a decrease in leptin levels stimulates appetite. There is a theory that olanzapine can at least partially stimulate food intake by reducing leptin levels. Acute administration of olanzapine also changes the animal response at the glucose and insulin levels in the glucose tolerance test, which is directly linked to the effect of olanzapine on food intake and weight gain. In contrast to olanzapine, the acute effects of the PDE10 inhibitors of the invention on metabolism (e.g. leptin, insulin and glucose changes during metabolic challenge in standard animal models) as well as in food intake, body weight and energy homeostasis Of the PDE10 inhibitors of the present invention provide evidence for the pharmacological benefits of PDE10 inhibitors as antipsychotics in terms of lower side effects.

The compositions of the present invention may be administered in combination, co-administration or sequential administration in combination with one or more additional therapeutic agents. Suitable additional therapeutic agents (i. E., Adjuvants) include dopamine-D ₂ receptors and typical antipsychotic drugs that block serotonin 5HT ₂ receptors (such as haloperidol, flupenazine, chloropromazine) and atypical antipsychotics Drugs (e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone).

Compounds of the present invention can be assayed by measuring IC ₅₀ values by a modification of the two step method of Thompson and Appleman (see Biochemistry 10; 311-316; 1971). In short, ( ³ H) cAMP is added to cAMP and incubated with PDE10 and compounds of structure (I) at various concentrations. After a suitable incubation period, the reaction is terminated by heating. The mixture is then treated with snake venom phosphatase. The phosphatase hydrolyzes the AMP in the mixture, leaving unreacted cAMP intact. Thus, the percentage of inhibition can be determined by separating cAMP from the mixture and measuring its concentration (by radiography). By performing experiments at several concentrations using standard graphical means, it is possible to calculate the IC ₅₀ value. A detailed description of the actual techniques used for the IC ₅₀ analysis is described in the Examples below.

The reactants used in the examples described below may be obtained as described in the present application or may be those which are commercially available or commercially available by methods known in the art unless otherwise stated in the present application ≪ / RTI > Certain starting materials can be obtained, for example, by the methods described in PCT International Publication No. WO 2011/112828.

Optimal reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Generally, the reaction progress can be monitored, if necessary, by high pressure liquid chromatography (HPLC) or nuclear magnetic resonance (NMR) spectroscopy, and can be monitored by chromatography on silica gel and / or by recrystallization or precipitation To purify intermediates and products.

In one embodiment of the present invention, the present invention relates to a multistage synthesis method for preparing compound 1001, compound 2001 and compound 3001, as described in the general reaction schemes (I) and (II). In one embodiment of the present invention, the present invention provides a process for preparing a compound of the formula (II-a) according to the general reaction scheme (I)

In formula (II-a), Q is S or O,

X is Cl or Br,

R ¹ , R ² and R ³ are each independently C _1-6 alkyl;

Scheme (I)

Converting the boronic acid A1 to a carbaldehyde B1 through activation of a boronic acid using an activating reagent A2;

Converting the carbaldehyde B1 to an acetal Cl under acid catalysis using an appropriate orthoformate source;

Converting the acetal C1 to nitrile D1 via catalytic cyanation using a metal catalyst and a cyanide source;

Hydrolyzing D1 with a suitable acid to provide carboxylic acid E1;

Converting the carboxylic acid E1 to an amide F1 using a suitable base, a suitable coupling agent and an amine source;

Converting an amide F1 to a compound of formula (II) using an anionic coupling agent having a H1 structure,

M is a Group 1 metal, a Group II metal, Cu or Zn;

R, R ² and R ³ are each independently C _1-6 alkyl;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Separating the compound of formula (II-a) from the compound of formula (II-b) by chiral HPLC; And

Optionally converting the compound of formula (II-a) to a salt.

In a further embodiment of the method of general formula (I), Q is O.

In a further embodiment of the method of general formula (I), Q is S.

In a further embodiment of the method of general formula (I), X is Cl.

In a further embodiment of the method of general formula (I), X is Br.

In a further embodiment of the method of general formula (I), M is a Group 2 metal.

In a further embodiment of the method of general formula (I), M is Mg.

In a further embodiment of the method of general formula (I), R < ¹ > is methyl, ethyl or propyl.

In a further embodiment of the method of general formula (I), R < 1 > is ethyl

In a further embodiment of the method of general formula (I), R < ² > is methyl, ethyl or propyl.

In a further embodiment of the method of general formula (I), R < ² > is methyl.

In a further embodiment of the method of general formula (I), R < ³ > is methyl, ethyl or propyl.

In a further embodiment of the method of general formula (I), R < ³ > is methyl.

In a further embodiment of the method of general formula (I), R is butyl.

In a further embodiment of the method of general formula (I), the acid catalyst used to produce acetal Cl is para-toluenesulfonic acid monohydrate.

In a further embodiment of the method of general formula (I), a suitable orthoformate source is triethylorthoformate.

In a further embodiment of the method of general formula (I), the metal catalyst in the cyanation step is a cobalt salt.

In a further embodiment of the method of general formula (I), the metal catalyst of the cyanation step is CoCl ₂ .

In a further embodiment of the method of general formula (I), the cyanide source is trimethylsilyl cyanide.

In a further embodiment of the method of general formula (I), the suitable acid in the hydrolysis step is HCl.

In further embodiments of the method of general formula (I), a suitable base in the amidation step is triethylamine.

In further embodiments of the method of general formula (I), a suitable coupling agent in the amidation step is propylphosphonic anhydride.

In further embodiments of the method of general formula (I), the amine source is N, O-dimethylhydroxyamine hydrochloride.

In further embodiments of the method of general formula (I), the compound of formula (II-a) is compound 2001:

In further embodiments of the methods of general formula (I), the compound of formula (II-b) is compound 3001:

In another embodiment of the present invention, the present invention provides a process for preparing a compound of formula (H1) according to the general reaction scheme (II)

In formula (H1), M is a Group 1 metal, a Group 2 metal, Cu or Zn,

R, R ² and R ³ are each independently C _1-6 alkyl,

X is Cl or Br,

m is 1, 2, 3 or 4,

p is 1, 2, 3 or 4;

Reaction formula (II)

The process comprises reacting a solution of a lithium alkyl metal in a solvent solution to produce a lithium alkyl metal base from R _n -Li where n is 1, 2, 3, 4 or 5 and a metal halide (including M) step; And

G1 and a metal lithiate H1 mixed from a lithium alkyl metal base.

In a further embodiment of the method of general formula (II), R < ² > is methyl, ethyl or propyl.

In a further embodiment of the general reaction formula (II) process, R < ² > is methyl.

In a further embodiment of the method of general formula (II), R < ³ > is methyl, ethyl or propyl.

In a further embodiment of the method of general formula (II), R < ³ > is methyl.

In a further embodiment of the method of general formula (II), R is butyl.

In a further embodiment of the method of general formula (II), X is Cl.

In a further embodiment of the method of general formula (II), X is Br.

In a further embodiment of the method of general formula (II), M is a Group 1 metal.

In a further embodiment of the method of general formula (II), M is a Group 2 metal.

In a further embodiment of the method of general formula (II), M is Mg.

In a further embodiment of the method of general formula (II), M is Cu.

In a further embodiment of the method of general formula (II), M is Zn.

In a further embodiment of the method of general formula (II), the lithium alkyl metal base is a lithium alkylmagnesate base.

In a further embodiment of the method of general formula (II), the lithium alkyl metal base is Bu ₄ MgLi ₂ .

In a further embodiment of the method of general formula (II), the compound of formula (H1) is a compound of formula (H1-1)

In the formula (H1-1), M is a Group 1 metal, a Group 2 metal, Cu or Zn,

R is C _1-6 alkyl,

X is Cl or Br,

m is 1, 2, 3 or 4,

p is 1, 2, 3 or 4;

In a further embodiment of the method of general formula (II), the compound of formula (H1-1) is a compound of formula (H1-1a)

In a further embodiment of the method of general formula (II), the compound of formula (H1-1a) is a compound of formula (H1-1a-1)

In one embodiment of the present invention, the present invention relates to a multistage synthesis method for preparing compounds 1001, 2001, and 3001, as described in the general reaction schemes (III) and (IV) In one embodiment of the present invention, the present invention provides a process for preparing a compound of the formula (III-a) according to the general reaction scheme (III)

In formula (III-a), Q is S or O and X is Cl or Br;

Converting the boronic acid A1 to a carbaldehyde B1 through activation of a boronic acid using an activating reagent A2;

Converting the carbaldehyde B1 to acetal C1-1 under acid catalysis using an appropriate orthoformate source;

Converting the acetal C1-1 to nitrile D1-1 via catalytic cyanation using a metal catalyst and a cyanide source;

Hydrolyzing D1-1 with a suitable acid to provide carboxylic acid E1-1;

Converting the carboxylic acid E1-1 to the amide F1-1 using a suitable base, a suitable coupling agent and an amine source;

Converting an amide F1-1 to a compound of formula (III) using an anionic coupling agent having a H1-1 structure,

M is a Group 1 metal, a Group II metal, Cu or Zn;

R is C _1-6 alkyl;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Separating the compound of formula (III-a) from the compound of formula (III-b) by chiral HPLC; And

Optionally converting the compound of formula (III-a) to a salt.

In a further embodiment of the method of general formula (III), Q is O.

In a further embodiment of the method of general formula (III), Q is S.

In a further embodiment of the method of general formula (III), X is Cl.

In a further embodiment of the method of general formula (III), X is Br.

In a further embodiment of the method of general formula (III), M is a Group 2 metal.

In a further embodiment of the method of general formula (III), M is Mg.

In a further embodiment of the method of general formula (III), R is butyl.

In a further embodiment of the method of general formula (III), the acid catalyst used to produce C1-1 is para-toluenesulfonic acid monohydrate.

In a further embodiment of the method of general formula (III), a suitable orthoformate source is triethylorthoformate.

In a further embodiment of the method of general formula (III), the metal catalyst of the cyanation reaction step is a cobalt salt.

In a further embodiment of the method of general formula (III), the metal catalyst of the cyanation reaction step is CoCl ₂ .

In a further embodiment of the method of general formula (III), the cyanide source is trimethylsilyl cyanide.

In a further embodiment of the method of general formula (III), the suitable acid in the hydrolysis step is HCl.

In a further embodiment of the method of general formula (III), a suitable base in the amidation step is triethylamine.

In a further embodiment of the method of general formula (III), a suitable coupling agent in the amidation step is propylphosphonic anhydride.

In a further embodiment of the method of general formula (III), the amine source is N, O-dimethylhydroxylamine hydrochloride.

In a further embodiment of the method of general scheme (III), the compound of formula (III-a)

In a further embodiment of the method of general scheme (III), the compound of formula (III-b) is compound 3001.

In another embodiment of the present invention, the present invention provides a process for preparing a compound of formula (H1-1) according to general scheme (IV)

In formula (H1-1), M is a Group 1 metal, a Group II metal, Cu or Zn;

R is C _1-6 alkyl;

X is Cl or Br;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

The process comprises dissolving R _n -Li (wherein n is 1, 2, 3, 4 or 5) and a metal halide (including M) in a solvent to produce a lithium alkyl metal base solution step; And

G1-1 and a metal lithiate H1 mixed from a lithium alkyl metal base.

In a further embodiment of the method of general formula (IV), X is Cl.

In a further embodiment of the method of general formula (IV), X is Br.

In a further embodiment of the method of general formula (IV), M is a Group 1 metal.

In a further embodiment of the method of general formula (IV), M is a Group 2 metal.

In a further embodiment of the method of general formula (IV), M is Mg.

In a further embodiment of the method of general formula (IV), M is Cu.

In a further embodiment of the method of general formula (IV), M is Zn.

In a further embodiment of the method of general formula (IV), R is butyl.

In a further embodiment of the method of general formula (IV), the lithium alkyl metal base is a lithium alkylmagnesate base.

In a further embodiment of the method of general formula (IV), the lithium alkyl metal base is Bu ₄ MgLi ₂ .

In a further embodiment of the method of general formula (IV), the compound of formula (H1-1) is a compound of formula (H1-1a)

In a further embodiment of the method of general formula (II), the compound of formula (H1-1a) is a compound of formula (H1-1a-1)

An additional embodiment of the present invention relates to individual steps of the multistage general synthesis methods described in the above general reaction schemes (I), (II), (III) and (IV). The intermediates of the present invention are described in detail below. All substituents in the intermediates described below are as defined in the multistage method described above.

Preferred anionic coupling agents are selected from compounds having a structure according to the following formula (H1)

In formula (H1), M is a Group 1 metal, a Group II metal, Cu or Zn;

R, R ² and R ³ are each independently C _1-6 alkyl;

X is Cl or Br;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Preferred anionic coupling agents are selected from compounds having a structure according to the following formula (H1-1): < EMI ID =

In formula (H1-1), M is a Group 1 metal, a Group II metal, Cu or Zn;

R is C _1-6 alkyl;

X is Cl or Br;

m is 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

In another embodiment of the present invention, M is Mg.

Preferred anionic coupling agents are selected from compounds having a structure according to the following formula (H1-1a): < EMI ID =

In the formula (H1-1a), X is Cl or Br.

In another embodiment of the present invention, X is Cl.

In another embodiment of the present invention, X is Br.

In another embodiment of the present invention, the anionic coupling agent has the structure of the formula (H1-1a-1)

In another embodiment of the present invention, the preferred nitrile intermediate has the structure of formula (D1-1): < EMI ID =

In another embodiment of the present invention, the preferred acetal intermediate has the structure of formula (C1-1)

Example

In order that the invention may be more fully understood, the following examples are set forth. These embodiments are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. The reactants used in the following examples may be obtained as described herein or may be prepared from materials commercially available or commercially available by methods known in the art unless otherwise stated herein have.

Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions are readily selectable by those skilled in the art. In general, the reaction process can be monitored by high pressure liquid chromatography (HPLC) if desired and intermediates and products can be purified by chromatography and / or recrystallization or precipitation in the absence of carbon or carbon have.

In one embodiment of the present invention, the present invention relates to a multistage synthesis method for preparing compound 2001 as described in Examples 1-9.

Example 1

To a solution of 2-bromo-5-methyl-l, 3,4-thiadiazole A2-1 (13.1 g, 73.3 mmol), (4-formylphenyl) bromic acid by A1 (10.0g, 66.7 mmol), 2M K 3 PO 4 (66.7 mL, 133.4 mmol) the mixture is heated to 55 ℃ under nitrogen, followed by placement under vacuum and nitrogen three times, for several minutes each in turn was degassed in . Tetrakis (trimethylphosphine) palladium (1.54 g, 1.33 mmol) was added and the mixture was then degassed again. After heating at 80 < 0 > C for 18 hours, cooling to room temperature, the aqueous layer was separated. The mixture was washed with brine, and the residual organic layer was greatly reduced by distillation. Addition of heptane provided a solid which was collected by filtration to give 4- (5-methyl-1,3,4-thiadiazol-2-yl) benzaldehyde as a solid in 85% yield.

Example 2

B1-1 (1.05g, 5.14 mmol), EtOH (10mL), CH (OEt) 3 (1.1 eq) and para-toluene sulfonic acid monohydrate (5 mol%) was heated at 67 ℃ for 30 minutes. The solution was cooled and saturated aqueous NaHCO ₃ (10 mL) was added. The mixture was transferred to a separatory funnel with dichloromethane (20 mL). Additional water dissolves the solids, and the layers are separated. The organic layer was concentrated under reduced pressure to give a mixture of solid and oil. The mixture was redissolved in dichloromethane (10 mL) and the solution was washed with water (5 mL). Solvent removal provided C1-1a (1.29 g, 90% yield).

Example 3

During the addition of CoCl ₂ (5 mg), C1-1a (145 mg, 0.522 mmol) was stirred with TMSCN (100 μL, 1.5 eq) and dichloroethane (1 mL). The reaction was heated at 60 < 0 > C for 3.25 h. Saturated aqueous NaHCO ₃ (2 mL) and dichloromethane (5 mL) were added. The layers were separated and the organic layer was concentrated under reduced pressure to give D1-1a as an off-white solid (104 mg, 77% yield).

Example 4

A mixture of D1-1a (1.01 g, 3.90 mmol), 1,2-dichloromethane (5.0 mL), concentrated HCl (2.0 mL) and water (1.0 mL) was heated to 70 <0> C for 15 h. After cooling to room temperature, water (1 mL) was added. The organic layer was separated and additional water (5 mL) was added to the aqueous layer followed by extraction with dichloromethane (2 x 10 mL). The first organic phase was combined with the dichloromethane extract and the mixture was concentrated under reduced pressure to provide E1-1a as a tan solid (tan).

Example 5

Alternatively, steps may be taken to form E1-1a from B1-1a without isolation of purified synthetic intermediates.

At room temperature the reactor was charged with para-toluenesulfonic acid (catalytic amount) and B1-1a (100.4 g, 0.490 mol) with toluene. Ethanol and triethylorthoformate were charged, followed by rinsing with toluene, respectively. The batch was heated to 45 &lt; 0 &gt; C. Para-toluene (catalytic amount) was further added, and heating was continued for 2 hours. Anhydrous K ₂ CO ₃ was added and the batch was partially concentrated under vacuum. Toluene was added and the batch was again partially concentrated. The batch was filtered to remove the solid. The reactor and filter were rinsed with toluene.

The solution was charged with CoCl ₂ (catalyst) and TMSCN at 20 ° C. The batch was heated at 75 &lt; 0 &gt; C overnight. At 70-80 占 폚, the resulting mixture was slowly charged with methyl tert-butyl ether. The batch was cooled to room temperature, followed by filtration, and the cake was rinsed with methyl tert-butyl ether and water. The wet cake was briefly dried to obtain 154.6 g of D1-1a as a wet cake.

At 20-25 [deg.] C, the reactor was charged with the wet cake of D1-1a followed by concentrated HCl and water. The batch was heated to 60 &lt; 0 &gt; C for 3.5 hours. Celite and acetonitr were added, and the batch was filtered over Darco G60 carbon and celite. The reactor was charged with the filtrate and heated to 60-70 占 폚. Water was added slowly and then cooled to 25 &lt; 0 &gt; C. The solid was collected by filtration, washed with water and dried to provide 105 g of E1-1a (77% yield) as a white solid.

Example 6

The reactor was charged with E1-1a (117.2 g, 0.392 mol as a hydrate, 6.3% water) with N, O-dimethylhydroxylamine hydrochloride (61.5 g, 1.5 eq) and dichloromethane (936 mL). The mixture was stirred to form a slurry. Triethylamine (272 mL) was slowly charged over 15 minutes, resulting in a slight exotherm. Propylphosphonic acid anhydride (376 g as a 50 wt% solution in dichloromethane, 1.5 eq) was slowly charged for 1 hour. Water (470 mL) was charged over 10 minutes. The layers were separated and the aqueous phase was extracted using dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution and 1N HCl solution. The batch was concentrated to some extent under reduced pressure. This was repeated twice. The mixture was heated at 50 &lt; 0 &gt; C, seeded, heptane added and then cooled to room temperature. The solid was collected by filtration and washed with a mixture of isopropyl acetate-heptane. F1-1a was obtained with a yield of 88% and a purity of 99%.

Example 7

G1-1a

According to the process reported in PCT International Publication No. WO 2008/040669, 2- (4-chloro-3,5-dimethoxyphenyl) furan G1-1a was synthesized as follows. 3,5-dimethoxy-4-chloro-bromobenzene (5g, 20 mmol), 2- furyl boronic acid (2.45 g, 21.9 mmol) and 2M Na ₂ tetrahydro a flask containing a CO ₃ (25 mL) Furan (50 mL) was added. The mixture was degassed by alternately placing under vacuum and excitation three times for several minutes each. Tetrakis (triphenylphosphine) palladium (0.46 g, 0.4 mmol) was added and the mixture was again degassed and then heated at 60 ° C for 17 hours. Volatiles were removed in vacuo, then methanol (10 mL) was added and the slurry was stirred at 60 [deg.] C for 2 hours. The mixture was cooled to room temperature and the solids were collected. The solid was slurried in hot methanol and then filtered and dried to give 2- (4-chloro-3,5-dimethoxyphenyl) furan (3.18 g, 67% yield).

Example 8

All solvents were degassed by sparging using N ₂ for a minimum of 20 minutes. To tetrahydrofura (39.0 mL) in a clean dry flask (small exotherm) was added MgBr ₂ .Et ₂ O (3.91 g, 15.2 mmol) to provide a slurry after cooling to room temperature. The mixture was cooled to -10 ° C and a solution of n-BuLi (16.81 g, 2.62 M solution in hexane) was added via syringe over 34 minutes. After stirring at -10 ° C for 1 hour, a solution of G1-1a (11.61 g, 48.6 mmol) in tetrahydrofuran (34.8 mL) was added at constant rate over 60 minutes. The solution was allowed to warm to room temperature and stored overnight under N _2.

To a separate flask was added a solution of F1-1a (12.48 g, 38.9 mmol) in toluene (100.0 mL) and tetrahydrofuran (25.0 mL). The solution was cooled to -23 DEG C and the anion solution (prepared above) was added over 2 hours. A solution of acetic acid (7.2 mL) in water (67 mL) was added over 11 min during which time the temperature was increased to -10 &lt; 0 &gt; C. The reaction was warmed to 50 &lt; 0 &gt; C and the water phase was removed. Water (67 mL) was added and the organic phase was collected and concentrated under reduced pressure. Chromatography on silica gel (70% isopropyl acetate-heptane) provided 12.8 g of compound 1001 (66% yield).

Example 9

Chiral preparative HPLC was performed on a Waters 2996 diode array detector at 35 ° C and a Waters Alliance 2695 instrument equipped with a Phenomenex Lux 5μ Amylose-2, 10.0 × 150 mm column. A mobile phase of acetonitrile: 2-propanol: methanol (71: 4: 25 v / v / v) was used. The detection wavelength was 274 nm. The run time was 7 minutes. Peak 1 corresponding to compound 2001 was eluted at 4.5 min. Peak 2 corresponding to 3001 was eluted at 5.2 minutes.

-88.9°(c=0.8, DMSO)(USP <781>)이었다. 화합물 3001에 대한 선광성을 측정하였더니,

+91.2°(c=0.9, DMSO)(USP <781>)이었다.The optical rotation of each enantiomer under the USP standard was measured. The optical rotation was measured for Compound 2001

-88.9 [deg.] (C = 0.8, DMSO) (USP <781>). When the roundness of the compound 3001 was measured,

+ 91.2 [deg.] (C = 0.9, DMSO) (USP <781>).

Example 10

Single Crystal Production of Enantiomeric Compound 2001

Compound 2001 (5 mg) was dissolved in 1,4-dioxane (10 [mu] L) at ambient temperature to produce a clean solution. The solution was then frozen, and the sample was left in the freezer for about 1 day to produce crystals. The sample was kept at ambient temperature for about 12 days to generate additional crystals. Using some of these crystals, seeding of the individual ambient temperature solution of compound 2001 (13 mg) in 1,4-dioxane (25 μL) resulted in immediate precipitation of crystals throughout the sample . The crystals were isolated / carefully separated from the Paratone-N oil.

Example 11

X-ray powder diffraction of the enantiomeric compound 2001

A colorless platelet of C ₂₉ H ₃₁ ClN ₂ O ₇ S [C ₂₅ H ₂₃ ClN ₂ O ₅ S, C ₄ H ₈ O ₂ ] having dimensions of approximately 0.200 × 0.200 × 0.020 mm was cut into fibers fiber in a random orientation. Preliminary tests and data collection were performed using a Cu Kα line (λ = 1.54178 Å) on a Rigaku Rapid II diffractometer equipped with a counterpoint optical system. Refinement was performed using SHELX2013.

=2n;

=2n;

=2n의 조건들의 체계적인 존재로부터, 그리고 연이은 최소자승법 정교화로부터, 공간군을 측정하였는데, P2₁2₁2₁ (no. 19)이었다. Using the setting angle of 29360 reflections in the range of 2 ° <θ <63 °, the cell constants for data collection from the least-squares refinement and the orientation matrix orientation matrix. The refined mosaicity from DENZO / SCALEPACK was 0.99 [deg.] Indicating a suitable crystalline quality. The space group was measured by the program XPREP.

= 2n;

= 2n;

From the systematic presence of the conditions of = 2n, and from the subsequent least squares refinement, the space group was measured P2 ₁ 2 ₁ 2 ₁ (no. 19).

Data were collected and the maximum 2 [theta] value was 126.8 [deg.] At a temperature of about 150 +/- 1 K. [

Data reduction

We integrated the frames using HKL3000 [8]. A total of 29,360 reflections were collected, of which 4436 were unique. Lorentz and polarized calibration were applied to the data. The linea absorption coefficient was 2.315 mm ^-1 for the Cu Kα line. Empirical absorption corrrection using SCALEPACK was applied. The transmission coefficient was in the range of 0.519 to 0.955. We averaged the intensity of equivalent reflections. The agreement factor for the mean was 6.2% based on intensity.

Structure Solution and Refinement

Scattering factors were drawn from [International Tables for Crystallography]. Of the 4436 reflections used for refinement, only the reflections with Fo2> 2σ (Fo2) were used to calculate the fit residual R. A total of 3852 reflections were used for the calculation. The final refinement cycle included 365 variable parameters and converged to unwighted and weighted agreement factors of 0.0488 and 0.1044, respectively (the largest parameter shifts were &lt; RTI ID = 0.0 > Less than 0.01 times the estimated standard deviation).

The standard deviation of the unit weight (goodness of fit) observation was 1.079. The highest peak in the final difference Fourier had a height of 0.320 e / Å 3. The minimum negative peak had a height of -0.305 e /? 3. The Flack factor for the measurement of the absolute structure is refined to -0.007 (10).

Measured X-ray powder diffraction (XRPD) pattern

PowderCell 2.3 and unit cell parameters from atomic coordinates, space group, and single crystal structures were used to generate XRPD patterns measured against Cu radiation. Because single crystal data were collected at low temperatures (about 150 K, e.g., 150 10 K or 150 1 K), the peak shifts were observed at room temperature in the experimental powder diffraction pattern (especially at room temperature Powder diffraction pattern).

ORTEP and Packing Diagrams

Using the ORTEP III program in PLATON, an ORTEP diagram was produced. The atoms were replaced with a 50% probability of anisotropic thermal ellipsoid. The chiral center evaluation was performed with the PLATON software package. The absolute configuration was evaluated using the molecular chirality rule manual. Using the Mercury 3.1 visualization package, packing diagrams and additional drawings were produced.

The molecular structure of the compound 2002 was confirmed by measuring the single crystal structure. The structure was determined to be a dioxane solvate consisting of one compound 2001 molecule and one dioxane molecule in the asymmetric unit. As a result of determining the absolute structure from the crystal structure, it was S arrangement in C12.

Example 12

PDE10 selectivity of Compound 1001

The PDE assay medium consisted of the following materials (final concentration): 50 mM Tris-HCl; 8.3 mM MgCl _2; 1.7 mM EGTA; 0.5 mg / mL bovine serum albumin (BSA); And substrate (H-cAMP or H-cGMP). BSA was a frozen powder, essentially free of fatty acids, and a product of Sigma (A6003) with a purity of at least 96%. 1 [mu] l of compound 1001 and 89 [mu] l of assay medium in 100% DMSO was added to a 96-well SPA plate and incubated at 30 [deg.] C for 1 minute. Analysis was initiated by the addition of 10 [mu] l of PDE10 and incubated for 21 minutes. Then, 50 [mu] l SPA beads were added, the plate sealed, stirred and incubated for 1 hour at room temperature. Plates were then counted with a Wallac 1450 Microbeta Trilux plate scintillation counter. For the PDE10 IC ₅₀ experiments, the substrate was 125 nM H-cGMP. For selectivity experiments, the substrates were 37 nM H-cAMP for PDE 3, PDE4, PDE 7 and PDE 8; And 37 nM c-GMP for PDE1, PDE2, PDE5, PDE9, PDE10 and PDE11. In all cases, substrate concentrations were below K _M. The substrate consumption was less than 6%, indicating that substrate concentrations did not change significantly during the analysis period.

The IC ₅₀ value was derived by fitting the data to a 4-parameter logistic model: F = ((AD) / (1 + ((x / C) B))) + D F is fractional activity, A is the activity in the absence of inhibitor, B is Hill slope, C is IC ₅₀ , and D is the limit of activity in an infinite inhibitor. At less than 50%, no analysis was performed and the IC ₅₀ was higher than the highest concentration.

Example 13

PDE10 Inhibitory Efficacy of Compound 2001

Using the same procedure as used in Example 12, the IC ₅₀ of Compound 1001, Compound 2001 and Compound 3001 were measured. The two enantiomers, Compound 2001 and Compound 3001, were over 99% pure by chiral chromatography. All three compounds were tested in the same experiment. The IC ₅₀ values of inhibition of PDE10 by OMS643762 and its enantiomers, OMS643772 and OMS643773, are given in Table 2.

Inhibition of human PDE10 by compounds 1001, 2001 and 3001 compound IC ₅₀  (nM) 95% confidence interval (nM) IC for racemate ₅₀  ratio 1001 0.62 0.50-0.77 One 2001 0.44 0.32-0.49 0.71 3001 5.8 0.42-7.8 9.4

Although the two enantiomers of compound 1001 are potent inhibitors of PDE10, compound 2001 is unexpectedly 13.2 times more potent than compound 3001.

Although the embodiments of the present invention are described in the specification for the purpose of illustration, it will be understood that various modifications may be made without departing from the spirit and scope of the present invention. Accordingly, the invention is not limited except as by the appended claims.

All US patents, US patent publications, US applications, foreign patents, overseas applications, and non-patent literature cited in this specification are herein incorporated by reference in their entirety, unless otherwise indicated. Lt; / RTI &gt;

Claims (16)

Or a pharmaceutically acceptable salt, solvate or prodrug thereof.

3. The compound of claim 1 which is enantiomerically pure.
The compound according to claim 1, which is substantially free of the opposite enantiomer.
The compound according to claim 1, which comprises at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the desired enantiomer.
A compound having the following structure in crystal form:

6. A compound according to claim 5 having an X-ray powder diffraction pattern comprising a peak at (at peak values) as measured using CuKa radiation at about 150K.
6. The compound according to claim 5 having an X-ray powder diffraction pattern substantially identical to that shown in Fig.
8. A pharmaceutical composition comprising a compound of any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.
A method of inhibiting PDE in a warm-blooded animal comprising administering to said animal an effective amount of a compound of any one of claims 1 to 7 or a pharmaceutical composition of claim 8.
A method of treating a neurological disorder in a warm-blooded animal having a neurological disorder,
Comprising administering to said animal an effective amount of a compound of any one of claims 1 to 7 or a pharmaceutical composition of claim 8,
The neurological diseases are selected from the group consisting of psychotic disorder, anxiety disorder, Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobia, Sleep disorders, pain, Tourette's syndrome, schizophrenia, delusions, epilepsia, aphasia, Bell's palsy, cerebral palsy, cerebral palsy, A psychotic disorder, delusional disorder, bipolar disorder, post-traumatic stress disorder, drug-induced psychosis, panic disorder, obsessive-compulsive disorder, Attention-deficit disorder, disruptive behavior disorder, autism, depression, dementia, epilepsy, insomnia and multiple sclerosis. &Lt; / RTI &gt; Law.
11. The method of claim 10, wherein the neurological disease is a manifestation disease.
11. The method of claim 10, wherein the neurological disease is post-traumatic stress disorder.
A process for preparing a compound of the formula (II-a) according to the general reaction scheme (I)

In formula (II-a), Q is S or O,
X is Cl or Br,
R ¹ , R ² and R ³ are each independently C _1-6 alkyl;
Scheme (I)

Converting the boronic acid A1 to a carbaldehyde B1 through activation of a boronic acid using an activating reagent A2;
Converting the carbaldehyde B1 to an acetal Cl under acid catalysis using an appropriate orthoformate source;
Converting the acetal C1 to nitrile D1 via catalytic cyanation using a metal catalyst and a cyanide source;
Hydrolyzing D1 with a suitable acid to provide carboxylic acid E1;
Converting the carboxylic acid E1 to an amide F1 using a suitable base, a suitable coupling agent and an amine source;
Converting an amide F1 to a compound of formula (II) using an anionic coupling agent having a H1 structure,
M is a Group 1 metal, a Group II metal, Cu or Zn;
R, R ² and R ³ are each independently C _1-6 alkyl;
m is 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
Separating the compound of formula (II-a) from the compound of formula (II-b) by chiral HPLC; And
Optionally converting a compound of formula (II-a) to a salt.
14. The method of claim 13, wherein the compound of formula (II-a) is a compound having the structure:

A process for preparing a compound of the formula (III-a) according to the general reaction scheme (III)

In formula (III-a), Q is S or O and X is Cl or Br;
Scheme (III)

Converting the boronic acid A1 to a carbaldehyde B1 through activation of a boronic acid using an activating reagent A2;
Converting the carbaldehyde B1 to acetal C1-1 under acid catalysis using an appropriate orthoformate source;
Converting the acetal C1-1 to nitrile D1-1 via catalytic cyanation using a metal catalyst and a cyanide source;
Hydrolyzing D1-1 with a suitable acid to provide carboxylic acid E1-1;
Converting the carboxylic acid E1-1 to the amide F1-1 using a suitable base, a suitable coupling agent and an amine source;
Converting an amide F1-1 to a compound of formula (III) using an anionic coupling agent having a H1-1 structure,
M is a Group 1 metal, a Group II metal, Cu or Zn;
R is C _1-6 alkyl;
m is 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
Separating the compound of formula (III-a) from the compound of formula (III-b) by chiral HPLC; And
Optionally converting a compound of formula (III-a) to a salt.
16. The method of claim 15, wherein the compound of formula (III-a) is a compound having the structure:

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